As multiple new drugs like antibody-drug conjugates (ADCs) become available for SCLC, the critical research question will shift from *if* they work to *when* they should be used. Future biomarker strategies must focus on optimizing treatment sequences, considering factors like the drug's target and payload.

Data from a novel Nectin-4 ADC trial showed zero responses in patients with prior topoisomerase therapy. This strongly suggests that payload resistance, not just the ADC target, is a critical mechanism that will dictate future treatment sequencing.

A "tsunami" of antibody-drug conjugates (ADCs) are in development for ovarian cancer, but many share the same TOP1 inhibitor payload. This creates a significant future clinical challenge: after a patient progresses on one such ADC, it is unknown if another with the same payload will be effective, creating an urgent need for sequencing data.

When sequencing antibody-drug conjugates, clinical experience suggests that resistance to the chemotherapy payload is a primary driver of failure. Therefore, oncologists tend to avoid using another ADC with the same payload consecutively, preferring to switch both target and payload if possible.

The TROPION-PanTumor01 study showed that patients who progressed on the TROP2-ADC sacituzumab govitecan still achieved responses to a second TROP2-ADC, Dato-DXD. This suggests that targeting the same antigen with a different payload can overcome initial resistance, informing future treatment sequencing.

Experts question the efficacy of sequencing ADCs like EV (Nectin-4 target) and DV (HER2 target) because they share the same MMAE chemo payload. Since resistance is often tied to the payload, not the target antibody, switching targets may not overcome resistance, though anecdotal responses have been observed.

A significant clinical challenge is the sequencing of antibody-drug conjugates (ADCs). Retrospective data from large databases indicates that using a second TROP2-targeted ADC after a first one provides very limited efficacy, highlighting an urgent need for prospective trials to define optimal sequencing strategies and overcome resistance.

When sequencing antibody-drug conjugates (ADCs) for SCLC, resistance may be driven more by the cytotoxic payload (e.g., a topoisomerase 1 inhibitor) than the antibody's target antigen. This suggests prior exposure to a similar payload class could predict non-response, even when using an ADC with a different target.

Emerging data shows that a second ADC, particularly one with the same payload, often has limited efficacy. This suggests clinicians must be highly strategic in selecting the first ADC, as it may be their most impactful opportunity for this class of drugs.